This invention is directed to a combination therapy comprising the administration of a low molecular weight heparin such as tinzaparin and a platelet GPIIb/IIIa antagonist such as roxifiban for treating, preventing and reducing the risk of thromboembolic disorders.
Thromboembolic diseases, including stable and unstable angina pectoris, myocardial infarction, stroke and lung embolism, are the major cause of disability and mortality in most developed countries. Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) is the main platelet receptor for fibrinogen and other adhesive glycoproteins, including fibronectin, vitronectin and von Willebrand factor. Interference of ligand binding with this receptor has been proven beneficial in animal models of thromboembolic disease (Coller, B. S. GPIIb/IIIa Antagonists: Pathophysiologic and Therapeutic Insights from Studies of C7E3 FAB. Thromb. Haemost. 78: 1, 730-735, 1997), and in limited studies involving human subjects (White, H. D. Unmet Therapeutic Needs in the Management of Acute Ixchemia. Am. J. Cardiol. 80: 4A, 2B-10B, 1997; Tcheng, J. E. Glycoprotein IIb/IIIa Receptor Inhibitors: Putting EPIC, IMPACT II, RESTORE, and EPILOG Trials Into Perspective. Am. J. Cardiol. 78: 3A, 35-40, 1996).
The integrin GPIIb/IIIa, also referred to as the platelet fibrinogen receptor, is the membrane protein mediating platelet aggregation. GPIIb/IIIa in activated platelets is known to bind four soluble RGD containing adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The term xe2x80x9cRGDxe2x80x9d refers to the amino acid sequence Arg-Gly-Asp. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. GPIIb/IIIa antagonists represent an important new approach for anti-platelet therapy for the treatment of thromboembolic disorders.
Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks and in a variety of other vaso-occlusive disorders. When a blood vessel is damaged either by acute intervention such as angioplasty, or more chronically by the pathophysiological processes of atherosclerosis, platelets are activated and adhere to the disrupted surface and to each other. This activation, adherence and aggregation may lead to occlusive thrombus formation in the lumen of the blood vessel. Since the binding of fibrinogen to an activated membrane-bound glycoprotein complex (GPIIb/IIIa) is an obligatory component of normal aggregation, GPIIb/IIIa is an attractive target for an antithrombotic agent.
Antiplatelet therapy has been used in a wide variety of cardiovascular disease states and in conjunction with interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary angioplasty (PTCA). Available drugs, such as aspirin and ticlopidine (TICLID(copyright)), have shown efficacy in syndromes involving vascular occlusion, presumably due to sustained inhibition of platelet function. However, the inhibitory effects of aspirin and ticlopidine are dependent upon the agonist, which activates the platelet. For example, aspirin is effective in blocking platelet aggregation induced by agonists such as collagen that are dependent upon the cyclooxygenase pathway. It is however, less effective against concentrations of thrombin which can act by cyclooxygenase independent pathways. Likewise, the inhibitory effects of tidopidine, which inhibits ADP induced platelet aggregation, can be overcome by combinations of agonists.
The effect of heparin on blood coagulation is exploited clinically as an anticoagulant and antithrombotic drug. Heparin belongs to the group of polysaccharides known as glycosaminoglycans (GAGs), and is composed of alternating 1-4-linked hexuronic acid and D-glucosamine. Both the hexauronic acid and the glucosamine residues are sulfated in a complex pattern resulting in extensive structural variability. Because of its high negative-charge density, heparin is able to interact with clusters of basic amino acids on numerous proteins and cell membranes, such as coagulation proteinases, serine protease inhibitors, growth factors, lipoprotein and hepatic lipase, apolipoproteins B and E, adhesive matrix proteins, platelets, and endothelial cells.
Low molecular weight heparins (LMWHs), obtained from standard unfractionated heparin (UFH), are as effective as standard unfractionated heparin for prophylaxis and treatment of venous thromboembolism and have fewer side effects (Schafer A. I. Low molecular-weight heparin for venous thromboembolism. Hospital Practice, Jan. 15, 1997, pp. 99-106). The current available low molecular weight heparins include, for example, tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin and dalteparin (fragmin).
A combination therapy comprising the administration of a GPIIb/IIIa antagonist with either aspirin or a low molecular weight heparin is useful in the treatment of thrombotic disorders including atherosclerotic arterial disease, valvular heart disease, cerebrovascular disease such as stroke, atrial fibrillation, coronary artery disease such as myocardial infarction and unstable angina, coronary artery bypass grafts, peripheral vascular disease, thromboembolic complications of prosthetic cardiovascular devices such heart valves and vascular grafts. These combinations are also expected to be useful when coupled with endovascular stenting procedures, such as percutaneous transluminal coronary angioplasty, to prevent subsequent arterial thrombus formation and reocclusion.
A number of criteria must be considered when contemplating a combination therapy: (a) each agent demonstrates significant clinical benefits in various thromboembolic disorders; (b) both agents act at different mechanistic levels and with different capacities; (c) combination of the agents at adjusted doses could improve efficacy and/or safety. In that regard, a wealth of clinical experience exists, especially for UFH and intravenous platelet GPIIb/IIIa antagonists in acute coronary syndromes (ACS). The potential clinical benefit of the platelet GPIIb/IIIa antagonist abciximab in ACS was demonstrated in the pivotal xe2x80x9cEvaluation of c7E3 Fab in the Prevention of Ischemic Complicationsxe2x80x9d (EPIC) and xe2x80x9cEvaluation in Percutaneous transluminal coronary angioplasty to Improve Long-term Outcome with abciximab GPIIb/IIIa blockadexe2x80x9d (EPILOG) trials. In the EPIC trial, there was significant excess bleeding that occurred when UFH was used in its full dose with abciximab leading to the EPILOG trial, where a reduced dose of UFH was used. The lower UFH dosage led to an improved safety profile without compromising the efficacy observed in the EPIC trial. Similarly, the xe2x80x9cPlatelet Receptor Inhibition in Ischemic Syndrome Managementxe2x80x9d (PRISM) and the xe2x80x9cPRISM in Patients Limited by Unstable Signs and Symptomsxe2x80x9d (PRISM-PLUS) trials evaluated whether administration of aspirin (PRISM) or UFH plus tirofiban (PRISM-PLUS) would improve clinical outcomes in the management of unstable angina. The control group in PRISM-PLUS received intravenous UFH only. Tirofiban plus UFH was significantly more effective than UFH alone in reducing the incidence of death, myocardial infarction, or refractory ischemia within 7 days after randomization. This finding suggested improved efficacy following administration of the combination of UFH and a GPIIb/IIIa antagonist. Other trials of GPIIb/IIIa antagonists with adjusted-dose UFH are currently under investigation. The advantages of LMWHs over UFH are significant (as described hereinafter), therefore the combination of a LMWH with a platelet GPIIb/IIIa receptor antagonist has great potential benefits when combined at the right dose regimens.
One object of the present invention is to provide a method of treating thrombosis in a mammal comprising: administering to said mammal the combination in a therapeutically effective amount of (i) a GPIIb/IIIa antagonist selected from the group consisting of abciximab, eptifibatide, tirofiban, amifiban, lefradafiban, sibrafiban, orbofiban, xemilofiban, a compound of the formula (A): 
and a compound of the formula (B) (roxifiban): 
and (ii) aspirin, or the GPIIb/IIIa antagonist (i) and (iii) a low molecular weight heparin selected from the group consisting of tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin and dalteparin, wherein at least one of the antagonist and aspirin, or at least one of the antagonist and the low molecular weight heparin, is administered in a subtherapeutic amount.
Another object of the present invention is to provide a method of treating thrombosis in a mammal wherein the combination of (i) and (ii) or (iii) above are administered in amounts to provide a synergistic effect.
Another object of the present invention is to provide a method of treating thrombosis in a mammal by administering to said mammal the combination in a therapeutically effective amount of tissue plasminogen activator (xe2x80x9cTPAxe2x80x9d), and a GPIIb/IIIa antagonist compound of the formula 
wherein at least one of said agents is administered in a subtherapeutic dose.
Another object of the present invention is to provide a method for treating a condition selected from the group: acute coronary ischemic syndrome, thrombosis, thromboembolism, thrombic occlusion and reclusion, restenosis, transient ischemic attack, and first or subsequent thrombotic stroke comprising the subcutaneous administration of a sub-therapeutic dose of a low molecular weight heparin in combination with a sub-therapeutic dose of a platelet GPIIb/IIIa antagonist to a mammal at risk of developing one or more of said conditions.